Cycloaliphatic aldehydes and process for the preparation thereof

ABSTRACT

Racemic and optically active cycloaliphatic 2,2,6-trimethyl-cyclohexanecarboxaldehydes, also known as dihydrocyclocitral, are prepared by a novel process consisting in the cyclization of enol esters of formula ##STR1## wherein the wavy line defines a C--O bond of cis or trans configuration, X represents an acyl group or P(O)(OR) 2 , wherein R stands for a lower alkyl monovalent radical or an aryl, and Z represents a monovalent radical of formula ##STR2## by means of an acid cyclization agent.

BRIEF SUMMARY OF THE DISCLOSURE

The present invention relates to a process for the preparation ofracemic and optically active dihydrocyclocitral, which process consistsin cyclising by means of an acidic cylisation agent an enol ester offormula ##STR3## wherein the wavy line defines a C--O bond of cis ortrans configuration, X represents an acyl group of P(O)(OR)₂, wherein Rstands for a lower alkyl monovalent radical or an aryl, and Z representsa monovalent radical of formula ##STR4##

BACKGROUND OF THE INVENTION

2,2,6-Trimethyl-cyclohexanecarboxaldehyde, also known asdihydrocyclocitral, is a cycloaliphatic aldehyde of formula ##STR5##

Not only does it represent a useful intermediate in a variety of organicsyntheses but it constitutes a raw material for the preparation ofuseful end-products for the flavor and perfume industry as well as forthe preparation of pharmaceuticals, namely for carotenoids and steroidstype compounds (see in this respect European Patent Application No.118,809 published on Sept. 19, 1984).

Numerous methods for its preparation have been described in the priorart. M. de Botton [Bull. Soc. Chem. de France, 33, 2466-73 (1966)] hasdescribed the preparation of dihydrocyclocitral starting from2,2,6-trimethyl-cyclohexanone according to the following reactionscheme: ##STR6##

Earlier described methods are based on the hydrogenation of cyclocitral[Helv. Chim. Acta, 31, 417 (1948) and Helv. Chim. Acta, 34, 1160 (1951)]or on the oxidation of dihydrocyclogeraniol [Helv. Chim. Acta, 23, 529(1940) and Helv. Chim. Acta, 23, 1265 (1940)]. The substitution of aketonic oxygen atom by an hydrogen and a formyl group, a reaction of thetype

    R.sub.2 CO→R.sub.2 CHCHO

represents a useful approach in organic syntheses for which severalspecific reactants have been developed. However none of them givessatisfactory results in the case of the transformation of stericallyhindered ketones having a hydrogen atom in the alpha position to theketonic group. E. J. Corey and M. A. Tius [Tetrahedron Letters, 21,3535-8 (1980)] have described a method for the preparation ofdihydrocyclocitral starting from cyclohexanone, precisely by means ofone of these specific reagents, diphenyl-methoxy-methyl phosphine. Thenature of the reactant, however, renders the industrial scale-upapplication of this method rather problematic.

I have now discovered that dihydrocyclocitral could be obtainedaccording to a simple and economical process, which process has theadvantage of utilizing traditional reactants.

THE INVENTION

The instant invention relates to a process for the preparation ofdihydrocyclocitral both in its racemic and optically active form, whichprocess consists in the cyclisation by means of an acid cyclisationagent of an enol ester of formula (I).

Radical R, as defined above, represents a lower alkyl monovalent radicalor an aryl, It can represent a C₁ -C₆ alkyl radical, for example amethyl, an ethyl, a propyl or an isopropyl or a phenyl group. Xrepresents an acyl group of the type R'CO, R' being preferably a loweralkyl radical having from 1 to 4 carbon atoms.

According to a preferred embodiment of the invention, the cyclisation iscarried out on 3,7-dimethyl-octa-1,6-dien-yl acetate, on3,7-dimethyl-7-hydroxy-oct-1-en-1-yl acetate or on3,7-dimethyl-octa-1,7-dien-1-yl acetate. These esters, and thecorresponding dialkyl- and diarylphosphate esters also defined byformula (I), can be obtained from citronellal or hydroxycitronellalaccording to a process analogous to prior described ones [see forexample: J. Am. Chem. Soc. 72, 2617 (1950)]. For example, theirpreparation can be effected by treating citronellal orhydroxycitronellal with acetic anhydride in the presence of a basicreagent such as a tertiary amine, e.g. triethylamine, or in the presenceof an alkali metal carbonate, for instance, potassium carbonate.

3,7-Dimethyl-octa-1,7-dien-1-yl acetate can be prepared by dehydrationof hydroxycitronellal according to known techniques followed byesterification.

Acidic cyclisation agents include mineral or organic protonic acids oracids of Lewis type. Preferred cyclisation agents include sulphuric,phosphoric, polyphosphoric, methanesulfonic, acetic or trifluoroaceticacids, or, among the Lewis acids, tin tetrachloride, titaniumtetrachloride or boron trifluoride, for example.

The temperature at which the cyclisation reaction is carried out is notcritical and varies within a wide range of values. It is generallychosen as a function of the acidic agent utilized. Thus, good yields ofend-products have been obtained by operating at 0° C. by using sulphuricacid as acidic agent and 3,7-dimethyl-octa-1,6-dien-1-yldiethylphosphate as starting ester. Good yields have been also obtainedby treating 3,7-dimethyl-octa-1,6-dien-1-yl acetate with concentratedphosphoric acid or polyphosphoric acid at 100° C. Temperatures higher orlower than the above given limits can also be utilized.

Preferred embodiments of the present invention will be described indetails in the specific examples of preparation.

As indicated above, the process of the invention possesses clearadvantages over the prior known preparation methods with regard to thesimplicity of the operations required and the overall economy. Besides,the process of the instant invention possesses the advantage of enablingfor the first time the preparation of optically activedihydrocyclocitral, namely of the epimers of formula ##STR7##

These two anipodes represent novel chemical entities, the preparation ofwhich was not possible with the hitherto known processes.

Optically active dihydrocyclocitral derivatives (a) and (b) representuseful starting materials for the preparation of optically activeend-products, the interest of which lies in that their specificproperties differ, to a lesser or greater extent, from those of theirracemic counterpart. This is the case for a variety of biologicallyactive compounds for which the physiological centers of reception inhumans or animals are able to differentiate the specific nature of eachof the perceived enantiomers, as this is the case, for instance, inolfactory perception.

In the present stage of our knowledge, there is no single theory able toelucidate the phenomenon of olfactory perception. However, experiencehas often shown that only one of the optically active forms of a givencompound possesses the desired odorous fragrance properties, theracemate showing at best half of its odor intensity without howeverpossessing the same olfactive character. On the other hand, theclassical methods to resolve a racemate into its D and L components leadto a maximum of 50% of each of them. This renders the process highlyunfavourable and the direct industrial preparation of pure antipodesrepresents therefore a major challenge.

Epimers (a) and (b) are obtained according to the process of theinvention starting from optically active enol esters of formula (I). Infact, the cyclisation according to the invention occurs unexpectedly bycomplete retention of the configuration of the asymetric carbon atoms inposition 6. Starting from (+)- or (-)-citronellal, it is thus possibleto obtain the corresponding optically active enol ester intermediatesand subsequently enantiomeric dihydrocyclocitral.

(+)- and (-)-Citronellal represent active constituents in severalessential oils from which they can be extracted. The two products are onthe other hand available on the market at variable degree of purity.R(+)-citronellal can be obtained for instance from Chinese citronellaaccompanied by minor amounts of linalol and isopulegol.

The invention will be illustrated in the following examples wherein thetemperatures are indicated in degrees centrigrade and the abbreviationshave the meaning common in the art.

EXAMPLE 1 (±)-Dihydrocyclocitral starting from (±)-citronellal

a. 167 kg of acetic anhydride and 77 kg of potassium carbonate wereheated to 80° in a reaction vessel equipped with an introduction pumpand a condenser. 85 kg of (±)-citronellal were then added by means ofthe introduction pump during 40 min and the mixture was refluxed for 7hours. After cooling, 100 kg of toluene and 500 l of water were addedthereto and after separation of the organic phase the mixture was washedwith 100 l of water to give a solution of3,7-dimethyl-octa-1,6-dien-1-yl acetate in toluene accompanied by minorquantities of a diester of formula ##STR8##

b. To the obtained solution, there were added 100 kg of toluene and 200kg of 85% phosphoric acid and the resulting mixture was heated at 100°and stirred during 1 hour 3/4 during which period the starting materialhad completely reacted. The reaction mixture was then cooled to 15° and347 l of water were added. The organic phase was separated bydecantation and washed with 100 l of a 6% aqueous solution of sodiumbicarbonate while toluene was stripped off at a temperature of60°-80°/150-110 mb. 91 kg of raw dihydrocyclocitral were thus obtained.The product was further purified by distillation on residue(57°-73°/30-9 mb). (±)-Dihydrocyclocitral was finally obtained in a68.1% purity in a yield of 60.4% based on pure material (75.4 kg).

EXAMPLE 2 (±)-Dihydrocyclocitral starting from (±)-citronellal

a. A mixture of 112.6 kg of acetic anhydride, 8.5 kg of potassiumacetate and 56 kg of triethylamine was heated to 80° and, at thistemperature, added of 84.5 kg of (±)-citronellal (addition time: 40min). The mixture was kept refluxing for 7 hours and after cooling toroom temperature, 100 kg of toluene and 350 l of water were added. Theorganic and water phase were then separated and the desired enol acetateaccompanied by minor amounts of a diacetate of formula (II) was obtainedas toluene solution.

b. The resulting solution was diluted by adding to it 100 kg of tolueneand under stirring it was added of 200 kg of 85% phosphoric acid. Themixture was heated to 100° during 1 hour 40 min and, after cooling to15°, it was added of 300 l of water while the organic phase wasseparated and washed with a 6% aqueous solution of sodium bicarbonate.Toluene was stripped off at reduced pressure (45°-88°/200-100 mb) togive 92.2 kg of raw (±)-dihydrocyclocitral. A distillation on residue(40°-60°/40-50 mb) has enabled to obtain 76.6 kg of(±)-dihydrocyclocitral of a purity of 65.7% (yield: 65.6% based on thepure material).

The following table summarizes the results obtained in the course ofessays carried out by using other cyclisation acidic reagents.

    ______________________________________                                        Ex-                                                                           am-                           Temp. Theor. yield                              ple  X            Acid        [°C.]                                                                        [%]                                       ______________________________________                                        3    --P(O)(OC.sub.2 H.sub.5).sub.2                                                             H.sub.2 SO.sub.4                                                                          0°                                                                           60                                        4    CH.sub.3 CO  H.sub.2 SO.sub.4                                                                          0°                                                                           35                                        5    CH.sub.3 CO  CH.sub.3 SO.sub.3 H                                                                       0°                                                                           42                                        6    CH.sub.3 CO  TiCl.sub.4  0°                                                                           33                                        7    CH.sub.3 CO  BF.sub.3.O(C.sub.2 H.sub.5).sub.2                                                         0°                                                                           55                                        8    CH.sub.3 CO  H.sub.3 PO.sub.4 85%                                                                      100°                                                                         74                                        9    CH.sub.3 CO  PPA         100°                                                                         72                                        10   CH.sub.3 CO  F.sub.3 CCO.sub.2 H                                                                       80°                                                                          40                                        ______________________________________                                    

EXAMPLE 11 (±)-Dihydrocyclocitral

A mixture of 100 g of (+)-citronellal having an alpha²⁰ _(D) =+9.4°,132.5 g of acetic anhydride, 65.6 g of triethylamine and 10 g ofpotassium acetate was heated to 120° for 6 hours. After cooling to roomtemperature, 230 of toluene were added to the reaction mixture whereuponwater and an aqueous sodium bicarbonate solution were added to it. Theorganic phase was separated and poured onto an aqueous solution of 85%phosphoric acid (230 g) and the whole was heated to 100° during 90 min.After cooling, the mixture was washed with water and with an aqueousbicarbonate solution and finally concentrated. Simple distillation gave73.5 g of a product having a content of 87% of dihydrocyclocitral (76%trans, 11% cis), alpha²⁰ _(D) =+0.04° (pure). A further purification bydistillation on a Fischer type column gave a pure product whose contentof transisomer was 93%; alpha²⁰ _(D) =+0.05° (pure).

EXAMPLE 12 (-)-Dihydrocyclocitral

S(-)-citronellal, obtained by oxidation of S(-)-citronellol (origin:Fluka AG, Buchs, Switzerland), was converted into (-)-dihydrocyclocitralaccording to a process identical to that described in above Example 11.The product obtained had an alpha²⁰ _(D) =-0.06° (pure).

EXAMPLE 13 (±)-Dihydrocyclocitral starting from 3,7-dimethyl-oct-7-enal

a. A mixture of 16 g (0.16 mole) of acetic anhydride (1.2 g of potassiumacetate) and 7.8 g (0.078 mole) of triethylamine was added of 12 g(0.078 mole) of 3,7-dimethyl-oct-7-enal and was refluxed for 6 hours.After cooling to room temperature, water and toluene (40 ml) were addedand the two phases separated.

b. The organic phase was mixed with 30 g of 85% phosphoric acid and themixture was refluxed for 2 hours. After cooling to room temperature,water was added to the resulting mixture and the organic phase wasseparated, concentrated and bulb distilled (bath temperature: 150°/15-20mb). 9.5 G of (±)-dihydrocyclocitral of 74% purity were thus obtained.

3,7-Dimethyl-oct-7-enal, used as starting material in the processdescribed above, was prepared by dehydration of hydroxycitronellal bymeans of potassium hydrogen sulfate.

EXAMPLE 14 (±)-Dihydrocyclocitral starting from hydroxycitronellal

By carrying out the reaction as indicated in above Example 13, and byusing the reactants and quantities indicated below, there were obtained22.3 g of (±)-dihydrocyclocitral of 63% purity.

    ______________________________________                                        a.       hydroxycitronellal                                                                           25 g                                                           triethylamine  37 g                                                           acetic anhydride                                                                             75 g                                                           potassium acetate                                                                            2.5 g                                                 b.       85% phosphoric acid                                                                          60 g                                                  ______________________________________                                    

What I claim is:
 1. Process for the preparation of dihydrocyclocitralwhich comprises cyclising by means of an acidic cyclisation agent anenol ester of formula ##STR9## wherein the wavy line stands for a C--Obond of cis or trans configuration, X represents an acyl radical orP(O)(OR)₂, R being a lower alkyl monovalent radical or an aryl and Zrepresents a monovalent radical of formula ##STR10##
 2. Processaccording to claim 1 wherein the enol ester is3,7-dimethyl-octa-1,6-dien-1-yl acetate, 3,7-dimethyl-octa-1,7-dien-1-ylacetate or 3,7-dimethyl-7-hydroxy-oct-1-ene-1-yl acetate.
 3. Processaccording to claim 1 wherein the enol ester is3,7-dimethyl-octa-1,6-dien-1-yl diethylphosphate,3,7-dimethyl-octa-1,7-dien-1-yl diethylphosphate or3,7-dimethyl-7-hydroxy-oct-1-en-1-yl diethylphosphate.
 4. Processaccording to claim 1 wherein the acidic cyclisation agent is a mineralor organic protonic acid or an acid of Lewis type.
 5. Process accordingto claim 4 wherein the acidic cyclisation agent is acetic acid,trifuoroacetic acid, phosphoric acid, methanesulfonic acid, borontrifluoride or titanium tetrachloride.
 6. Process according to claim 5wherein the cyclisation is carried out at a temperature of between about0° and 100° C.
 7. Process according to claim 1 wherein the enol ester ischosen among the enantiomers of formula ##STR11## wherein X and the wavyline have the meaning set forth in claim 1 and the obtaineddihydrocyclocitral occurs in the form of one of its optically activestereoisomers of formula ##STR12##